The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca²⁺ and cAMP

Lee, G. S. et al. Nature 492, 123-127 2012

Speaker: Kuan-Jung Lin (林冠蓉)                                        Time:13:10~14:00, April.3, 2013

Commentator: Pei-Jane Tsai, Ph.D. (蔡佩珍老師)                Place: Room 601

Abstract:

Inflammasome activation results in caspase-1 activation, therby leading to the maturation and secretion of pro-interleukin 1b (IL-1b) and pro-IL-18. Some of the NLR (nucleotide-binding domain, leucine-rich repeat containing) family members are key mediators of theinflammasome. NLRP3 is activated by three common cellular events elicited by different stimuli: (1) potassium efflux; (2) the generation of ROS; (3) phagolysosomal destabilization and the release of endogenous mediators into the cytosol¹. Mutations in NLRP3 cause auto-inflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS)². However the linkage between the current model for NLRP3 inflammasome activation and the activation of CAPS-associated mutation in NLRP3 remains unclear. The authors found that calcium-sensing receptor (CASR) bound to extracellular Ca²⁺ or other CASR agonists and then activated NLRP3 inflammasome via increasing intracellular Ca²⁺ and decreasing cellular cyclic AMP (cAMP).  CASR activated NLRP3 inflammasome through phospholipase C, which hydrolyses phosphatidylinositol-4,5-bisphophate intodiacylglycerol and inositol trisphosphate (InsP₃). InsP₃ bound to InsP₃ receptor and thus induced release of Ca²⁺ from ER stores. The increasing intracellular Ca²⁺ promoted inflammasome assembling. Furthermore, spontaneous inflammasome activity was attenuated when the concentration ofCa²⁺ decreased in cells from CAPS patients. On the other hand, decreasing of intracellular cAMP resulted from CASR stimulation. cAMP bound to NLRP3 directly and decreased inflammasome assembling. CAPS-associated mutations in NLRP3 reduced the affinity for cAMP binding. Together, this study demonstrates that Ca²⁺ and cAMP play important roles in regulating NLRP3 inflammasome activation.

References:

1     Rathinam, V. A., Vanaja, S. K. & Fitzgerald, K. A. Regulation of inflammasome signaling. Nat Immunol 13, 333-332, doi:10.1038/ni.2237 (2012).

2     Masters, S. L., Simon, A., Aksentijevich, I. & Kastner, D. L. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease . Annual review of immunology 27, 621-668, doi:10.1146/annurev.immunol.25.022106.141627 (2009).